Managing Post-Transplant Refractory/Resistant CMV

Older antivirals for these severely immunocompromised patients are associated with serious toxicities; New agents look like better options.

BY CONNI B. KOURY

Cytomegalovirus (CMV) infection is the most common infectious complication in solid organ transplant and hematopoietic stem cell transplant (HSCT) recipients.

The incidence varies depending on the type of transplant, CMV serostatus of the donor and recipient, and the level of immunosuppression. Overall, about one-third of transplant patients will have CMV infection, which when left untreated, can progress to clinically severe and sometimes life-threatening disease. CMV infection more than doubles the risk for transplant loss and mortality, according to studies (Virology [Auckl] 2019;10:1178122X19840371. doi: 10.1177/1178122X19840371. eCollection 2019).

Resistant, Refractory Infection

Some post-transplant CMV patients will develop infection or disease that is refractory and/or resistant (R/R) to previous anti-CMV treatment. Outside of CMV retinitis, there had been no FDA antiviral drugs approved for post-transplant CMV infection and disease, including R/R CMV. These patients, therefore, have been treated empirically with existing antivirals that include the IV agents ganciclovir, foscarnet and cidofovir, and oral valganciclovir. The older agents have significant challenges to their use, including toxicities, that may lead to premature discontinuation, predisposition to development of resistance, and ultimately failure to control CMV infection.

One agent, letermovir (Prevymis, Merck), was approved in 2017 for CMV prophylaxis. It has a favorable safety profile and is available in IV and oral dosage forms, but is only indicated for adult recipients of an allogeneic HSCT.

“Fortunately, with appropriate use of antiviral therapy, both as prophylaxis and as treatment, R/R disease is rare,” said Camille Nelson Kotton, MD, FIDSA, FAST.

“But when it does occur, there is significant morbidity and mortality associated with it as these patients are the most vulnerable and immunocompromised and at the highest risk for complications. It is a dreaded and challenging situation,” said Dr. Kotton, who is the clinical director, Transplant & Immunocompromised Host Infectious Disease Group, Infectious Diseases Division at Massachusetts General Hospital, and an associate professor at Harvard Medical School, both in Boston. She presented an overview of posttransplant R/R CMV infection and unmet needs to the FDA’s Antimicrobial Drugs Advisory Committee (ADAC) in October, when they gave the nod to maribavir (Takeda), which is now approved to treat refractory CMV infection and disease.

Patients with R/R CMV have increased morbidity and mortality compared with patients who do not have R/R infection (Transplantation 2016;100[10]:e74-80). The treatment options have historically involved switching from oral valganciclovir to ganciclovir, increasing the dose of ganciclovir, or switching to foscarnet or cidofovir. High-dose ganciclovir is poorly tolerated due to neutropenia/cytopenias; forcarnet is associated with a risk for serious renal toxicity and electrolyte abnormalities;

and cidofovir carries serious renal and ocular toxicity risks. There is a significant unmet need for antiviral agents that are more effective, safer, more tolerable and easier to administer.

“Until now, as per the [CDC] guidelines, we would recommend either high-dose ganciclovir for mild to moderate disease. This, in my experience, does not work very well because many of the CMV mutations convey a high level of resistance to ganciclovir,” Dr. Kotton explained. “We’d have to use foscarnet, which has a high level of toxicity and requires hospitalization. Then you end up having to go among these treatments to see if something else is going to work better, but they all have the same framework of side effects and toxicities.”

Newer Antivirals

Letermovir and maribavir work by unique mechanisms of action and are not associated with significant myelotoxicity or nephrotoxicity. Letermovir targets the subunit pUL56 of the terminase enzyme complex, thereby inhibiting the terminal phase of the virus life cycle (Clin Infect Dis 2021;73[1]:156-160). When the FDA approved letermovir in 2017, for CMV prevention in CMV-seropositive HSCT recipients, it marked the first approval of a new anti-CMV agent since 2003.

In a pivotal phase 3 randomized, multicenter, double-blind, placebo-controlled study of adult CMV-seropositive people who had an allogeneic HSCT, patients were randomized 2:1 to letermovir or placebo and stratified by study site and high versus low risk (N=565) (N Engl J Med 2017;377[25]:24332444). Letermovir significantly lowered the risk for clinically significant CMV infection compared with placebo through week 48. Fewer patients in the letermovir arm (37.5%; 122/235) compared with the placebo arm (60.6%) developed significantly clinical CMV infection (defined as CMV disease or CMV viremia that required preemptive treatment), discontinued treatment or required an antiviral for CMV infection through week 24 post-transpant (P<0.001), the primary end point. Due to the agent’s specificity to CMV, additional prophylaxis would be required to prevent herpes simplex virus (HSV).

Maribavir is a competitive inhibitor of adenosine triphosphate binding to pUL97, a protein kinase essential for viral replication, and maribavir is now approved for R/R posttransplant patients. It shows antiviral activity against CMV, but not HSV 1 and 2, varicella-zoster virus, human herpesvirus-6 (HHV) and HHV-8 (Antiviral Res 2019;163:91-105). The ADAC unanimously recommended the approval of maribavir for patients with R/R post-transplant CMV, both those with and without genotypic resistance to the standard-of-care antivirals. It is currently the only agent approved for posttransplant CMV infections in R/R patients.

“I think many of us will very quickly switch away from foscarnet with the associated high toxicity, need for blood work to monitor electrolytes and creatinine, and sometimes three weeks or more in the hospital. All of this is phenomenally challenging for the patient and very expensive,” Dr. Kotton said.

The safety and efficacy of maribavir have been established across multiple phase 2 and 3 studies involving more than 1,500 subjects, according to data the company presented to the FDA advisory panel. The pivotal phase 3 study included a total of 352 patients with R/R CMV who were treated with 400 mg of maribavir twice daily (n=235) compared with those receiving investigator-assigned therapy (IAT) with ganciclovir, valganciclovir, cidofovir or foscarnet.

The primary end point, endorsed by the FDA, was confirmed CMV viremia clearance at week 8, according to Martha Fournier, MD, the executive medical director, Clinical Sciences, Takeda, who presented the efficacy data. The key secondary end point was a composite of CMV viremia clearance and symptom control. The comparator arm was designed to mimic real-world care, she said. Investigators were allowed to use one or two of the available CMV antivirals; however, combined therapy with cidofovir and foscarnet was prohibited, Dr. Fournier noted.

Maribavir demonstrated superior CMV clearance versus IAT at week 8, (56% vs. 24%; P<0.001). Dr. Fournier showed sensitivity analyses to support the robustness of the primary end point. These data included the finding that CMV viremia clearance at week 8 or at the time of study discontinuation or treatment switch was 60% in the maribavir group compared with 43.6% in IAT group (P=0.001). CMV viremia clearance at any time during treatment was 74% in the study group versus 52.1% in IAT (P<0.001), and CMV viremia clearance at week 8 regardless of alternate CMV antiviral strategy was 59.1% in maribavir-treated subjects versus 42.7% in IAT subjects (P=0.002). Dr. Fournier said results were consistent across subgroups. In the key secondary end point, the maintenance of viremia clearance and symptom control was 19% for maribavir compared with 10% in the IAT group (P=0.013).

Dr. Kotton noted that maribavir has an excellent safety profile as seen in the phase 3 study and previous studies, with the most common side effect being dysgeusia. Because it was well tolerated, patients were able to stay on maribavir 50% longer than with standard of care.

“Having led creation of international consensus guidelines on CMV for solid organ transplant for over a decade and a half, and understanding the intrinsic challenges in the field—especially with resistant/refractory disease—I am thrilled to have new therapeutic options,” Dr. Kotton said. “For the first time, we might be able to consider clinical trials involving combination therapy, especially in higher-risk situations. Anytime we have a new antiviral agent in the CMV sphere, we are very happy and excited as this is sure to be a game changer, and hopefully will save lives and improve the overall quality of many lives as well.” ■

Dr. Fournier is an employee of Takeda Dr. Kotton is a consultant to Merck, Takeda, Roche Diagnostics and Hookipa.